Friday, 8 May 2015

ClinicSpeak: when does progressive MS begin?

Moving beyond NEDA: preventing end-organ damage #ClinicSpeak #MSBlog #MSResearch"Mouse Doc's post this morning on retinal nerve fibre loss in early MS is a stark reminder that the progressive phase of MS is present from the earliest stages of MS. It is now clear that some MSers already have lost substantial brain, and retinal tissue, when they present with their first clinical attack of MS (CIS). Even a proportion of RISers (people with asymptomatic MS or radiologically isolated syndromes) have brain volume loss and subtle cognitive deficits when investigated. Therefore the idea that progressive MS begins later in the course of the disease is inaccurate. We simply have to accept that the pathological processes driving progressive MS (neuronal loss) are present from the earliest stages of the disease. The quicker we accept this the sooner the community will accept the responsibility of moving beyond NEDA (no evident disease activity) and start to focus on preventing end-organ damage (brain volume loss or atrophy) and promoting brain health as the new therapeutic target in MS. HCPs (healthcare professionals) need to take up the challenge and the responsibility of maximising the brain function and health of the MSers in their care. Why wouldn't MSers' want to maximise the health of their brains?"

112 comments:

All us MSers want to retain brain health and limit damage. This is a statement of the obvious. But you need to give us the tools to do this. There are a range of drugs which potentially provide neuroprotection e.g. Simvastin, testosterone for males, sodium channel blockers. However, the system the medical authorities have set up means they are unlikely to ever be become available. The only thing we can do is use the approaches from the early trials and buying the drugs on line. What would you do? Do you really expect us to wait another 10 years until all the required studies are completed? What would you do if you had progressve MS?

Nice post, but what does it mean? If I came to see you tomorrow after my first attack what could you offer me beyond the usual first line therapies? Is there a neuroprotective agent you could offer me?

By the time PPMSers present they have probably had the disease for quite a long time. We need to try and diagnose PPMS ASAP and realise that we are dealing with two processes; (1) inflammation and (2) neurodegeneration. We therefore need to go back to the drawing board with our trial design and starting planning combination therapy strategies to tackle PPMS. I am not in the camp that thinks PPMS is an intractable problem. And yes I think PPMS will respond to highly-effective DMTs if they are started early enough and the trials are done long enough to account for therapeutic lag. However, anti-inflammatories will not be enough we will need to add neuroprotective drugs on top of them. An obvious combination supported by data is rituximab and laquinimod.

Re "By the time PPMSers present they have probably had the disease for quite a long time. We need to try and diagnose PPMS ASAP..."The problem I see is that with its gradual onset and symptoms which have little impact initially, but which build over time, there is a lack of knowledge or incentive for GPs to refer people with a mixed bag of amorphous but comparatively or relatively mild symptoms/problems to a neurologist until things have reached a stage where the patient's life is being significantly impacted and it becomes very clear that something is wrong. Of course, with no acute relapses to speed things up, such referrals to specialists then get treated as not urgent, and you languish at the bottom end of the waiting list, while all the time MS is silently doing its damage, just like a termite infested house - looks fine on the outside but rotting away where it can't be seen. Then by the time you finally get diagnosed, a heap of irreversible damage has been done, which no drugs will be able to fix.

So maybe the first step to halting the PPMS "saga" is to start educating GPs about the insidious slow onset of PPMS, and getting them to refer patients to specialists a lot sooner. Then there may be a chance of combination DMTs (if they ever get proven in trials) having some benefits. No diagnosis = no chance of treatment, regardless of what meds might become available.

It's all very well, but I didn't go to my GP for 5 months at onset and then only when I could hardly walk. I was put on a waiting list for a major teaching hospital. I deteriorated so badly my GP got me to see another specialist at another hospital the next day. I didn't get a diagnosis until 7 months after my first symptoms and a year after my first ever migraine.

After symptoms started in 2008, I finally saw neuro in 2011 - cervical lesion only seen and clear LP. DX is suspect PPMS and am currenlty waiting for "more evidence" before I get firm diagnosis. When I read this blog phrases such as "time is brain" and Prof G's post above I feel so frustrated with my neuros "wait and see" approach. I have asked my GP to refer me to Prof G and I am told he cant refer to Engand when the service is provided for in N.Ireland already.

As a late onset MSer, several of my symptoms were attributed to (a) just getting older and (b) menopause. It took six months from when my referral was sent to the hospital before I finally got to see the neurologist in 2013, and if I hadn't made direct contact myself with the specialist in an attempt to see him privately outside our public health system, I would probably still be waiting to see him. So, some five or six years after first symptoms appeared (hindsight is a wonderful thing) I finally get a diagnosis, and was EDSS 3+ at diagnosis, with multiple spinal lesions and 15+ brain lesions. Thus in many ways those who have acute relapses or a CIS might be considered the lucky ones as at least their relapse (or CIS) results in tests being done that produces a diagnosis and access to treatment (provided their neuro actually believes in hit hard, hit early!).

Hi Prof GI've asked previously regarding testosterone as a neuroprotectiveWhat is your thoughts? Is someone has borderline low T would it be worth looking into this as a neuroprotectiveI know tjeres risks involved but look at the pml risks with some dmts

MouseDoctor2Friday, May 08, 2015 11:15:00 a.m.There needs to be a lot more work before any neuroprotective effect of testosterone supplementation is established.

Isn't this the same message for every therapy researchers are looking at - anti-virals, simvastin, sodium blockers, stem cells.... Why can't MS researchers ever finish a job, it seems that the purpose of MS research is to keep dong studies, rather that improving the lot of people with MS.

Why can't researchers finish the job? Simple. Money.You need proper evidence before you can do anything.Trying to do this on your own without the backing of pharma big bucks or a very wealthy benefactor is a very very hard task but it may prod pharma into action.I'm not a medic, all the rest of us non medics can do is produce the best research we can and hope it is taken up and moved forward. that's what this group tries to do with the help of our clinical colleagues. If we had the resource of pharma, we could improve the lot of MSers quicker but sadly we don't.

We are convinced phenytoin is neuroprotective on the basis of evidence so far but it's still early days.It is not possible for medics to prescribe phenytoin on a "compassionate" basis if it isn't licensed for the application.

And being neuroprotective should slow disability?The issue with all this is the variability of the disease for some people it will look like a huge help for others it won't because of their rateEven though it may be working

Wow Don Giovannoni, who’d have thought that curing MS was as easy as giving a few doses of alemtumab? I mean three or four whacks of the old Camptath-1H, a drug that has been hanging around for nearly fifty years, and Bob’s your uncle. It seems this MS malarkey was seriously simple to fix because, as you keep reminding us, give this toxic infusion early enough and then the sufferer will be cured of their multiple sclerosis forever. It is that simple.

Gosh, it seems this disease was actually really easy to sort out. There is no need for personalised medication as now a simple blunt instrument licensed by the good billionaires at Sanofi will eradicate a disease that has hitherto been labelled a seriously complex. You sure made monkeys out of the naysayers, Don Giovannoni.

Get in there son! You cracked it! You’ve made something that we don’t know why it even happens, a thing of the past if you get some of the good old Genzyme's toxic stuff pumped into your veins quickly enough. Man, the pollsters got the UK election forecasts completely wrong and made us feel totally stupid this morning. You’ve done the same thing to clinical care as we know it. We applaud you, sir.

Dr Dre, what happens if does cure MS in some people? I had my last dose over 10 years ago and as far as I am concerned I am cured. No relapses, no MRI activity, mobile, fully employed, married, children, happy and healthy. You shouldn't be so flippant about such a serious issue a lot of people with MS may not consider alemtuzumab because of comments like yours.

1.a person who believes that people are motivated purely by self-interest rather than acting for honourable or unselfish reasons."some cynics thought that the controversy was all a publicity stunt"a person who questions whether something will happen or whether it is worthwhile."the cynics were silenced when the factory opened"synonyms: sceptic, doubter, doubting Thomas, scoffer; More

2.a member of a school of ancient Greek philosophers founded by Antisthenes, marked by an ostentatious contempt for ease and pleasure. The movement flourished in the 3rd century BC and revived in the 1st century AD.

Dr Dre, I am very glad to hear you are so thrilled about Labour getting what it deserved. Let's hope the conservatives save the NHS from the inefficiencies of the past and people with MS from lack of access to treatment. You may or may not know that we in the UK are near the bottom of the treatment league tables in Europe.

Re: "Prof G, if MS is so complex how can it be cured and stabilised so easily? It makes no sense."

Well if the autoimmune dogma is correct it may not be that complex. Rebooting or resetting your immune system may be all that is necessary. That is the hypothesis underpinning induction therapies (cladribine, alemtuzumab, HSCT, anti-CD20, etc.). Induction therapy only addresses autoimmunity and not neurorestoration. If the nervous system has acquired too much damage prior to treatment this will persist, hence the need for early treatment.

On the other side of the coin the autoimmune dogma may be wrong. MS may be caused by a virus. If that is the case the treatments may not work, unless the virus resides in the compartment hit by the treatments targeting the immune system.

Dismissing the long-term data in relation to alemtuzumab and HSCT is premature; a proportion of MSers treated with these therapies are doing remarkably well. Complex or simple, the data speaks for itself.

Maybe the autoimmune theories and the viral theories are both correct, and perhaps some of the other theories floating around out there may also have some validity, and maybe this is why some drugs work for some people and not others, while some people claim "miracles" on some of the MS diets, and other have success with different diets, and some get no benefit at regardless of what they eat. Until the causes of MS have been established, it's all a bit of a lottery as to whether anything you try will be effective - if you are lucky the first thing you try may be just what your own particular version of MS needs. If not, then you just keep road-testing different collections of side effects in the hope that at some point you will stumble onto what works for your MS.

Dre sure knows how to get responses. I've never seen so many so railed up.

I do think the basic question he/ she asked is a good one and well answered by Prof G. His sarcastic tone, though, is like so public school w*anker trying to belittle those around him/ her. Be respectful, Dre, but you ought not to be censored.

Prof G,Your thoughts on treating a newly diagnosed female RRMS patient, EDSS 0, few brain & no spine lesions? Is there a place for interferon treatment? Or should Lemtrada be considered even at this stage?Many thanks

Re: "Is there a place for interferon treatment? Or should Lemtrada be considered even at this stage?"

There is a place for both; it is all about choice and risks and benefits. Both these therapies have a license to be used as 1st-line treatments for active RRMS. What decides which one is used is very complex. I suggest you discuss this with your neurologist.

Prof G regarding catching ppms earlyWhat would you do for a patient you know has very early ppms? Would you keep them as RRMS and treat in the interim with something like lemtrada?Is there any times lemtrada has been tried and or succesful in ppms? Or is hsct etc the way to go

Thank you Prof G. I am on Rebif & considering Lemtrada. My neurologist says the choice is ultimately mine. I do not wish to acquire brain atrophy or subclinical damage & missing my window of opportunity. He says there will be obvious clinical & radiological signs before this window has passed. Do you agree, or do I run the risk of missing this window by remaining on a less efficacious treatment? Anon, 1:23pm

There maybe one problem in the idea because this argues that astrocytes are antigen-presenting cells and to present antigen to T cells you need to express MHC class II and when you look properly and I mean properly (e.g. by immuno electron microscopy) you find that they do not do this, despite the many claims in the literature. Next even i they did express MHC class II, this would be in response to say gamma interferon and therefore it would be secondary to the cause.

However not to say this is not involved,

Thought you may be interested in this one.

Mult Scler. 2014 Oct;20(12):1593-601. doi: 10.1177/1352458514528758. Epub 2014 Apr 14.Beta2-adrenergic agonist use and the risk of multiple sclerosis: a total population-based case-control study.Tsai CP, Lin FC, Lee CT.OBJECTIVE: The aim of this study was to investigate whether the use of fenoterol, a beta2-adrenergic agonist, was associated with multiple sclerosis (MS) risk by conducting a total population-based case-control study in Taiwan.METHODS:A total of 578 patients with newly diagnosed MS who had a severely disabling disease (SDD) certificate between January 1, 2002 and December 1, 2008 comprised the case group. These cases were compared with 2890 gender-, age-, residence-, and insurance premium-matched controls. Fenoterol use was analyzed using a conditional logistic regression model that controlled for asthma, chronic obstructive pulmonary disease (COPD), salbutamol and steroid use.RESULTS: Compared with the group of people who did not use fenoterol, the adjusted odds ratios were 0.67 (95% confidence interval (CI) = 0.48-0.93, p = 0.016) for the group prescribed fenoterol below 2.25 cumulative defined daily dose (cDDD) and 0.49 (95% CI = 0.33-0.71, p < 0.001) for the group with a cumulative fenoterol use of more than 2.25 cDDD. The dose-response relationship was similar within the non-asthma patients. The associations were similar between males and females, but differences between age groups were observed.CONCLUSIONS: The results of this study suggest that fenoterol use may reduce the risk of MS.

Yes I saw this and it adds to the theory that beta2-agonists may be of value in controlling the disease process which is one of the reasons why I chose to try Albuterol add on therapy.

Astrocytes acting as antigen presenting may not be the cause of acute inflammation, but it seems that astrocytes that lack the beta 2 adrenergic receptor may be diving progressive disease. In fact there is a disease in dogs that closely resembles MS and the astrocytes from dogs with this disease lack this receptor. This is an effect of viral infiction (sound familiar):

"Studies with canine distemper virus (CDV) suggest that a virus might be involved. CDV is a morbillivirus that preferentially infects astrocytes and causes a chronic inflammatory demyelinating disease in dogs that closely resembles MS [13]. Interestingly, CDV dramatically reduced the number of b-adrenoceptors in infected C-6 rat glioma cells [14], and b 2 -adrenoceptors were not present on astrocytes in dogs with CDV encephalitis but were present on astrocytes in dogs with other inflammatory CNS diseases [15]. Attempts to identify CDV antigen and genome in MS brain specimens have been unsuccessful [16]. However, a similar viral infection might be responsible for the disappearance of b 2 -adrenoceptors from astrocytes in MS."

Another thing about this theory that makes sense to me is the long tracks would be effected first because the energy supplied by astrocytes are vital in supporting the health of these long axons. If astrocytes are unable to nourish these long tracks they would be the first to show signs of disability which seems to be the case in MS.

if using as an add-on the question is why add on to a weakly effective treatment as opposed to a highly active therapy. You have a point about energy being a problem for nerves and astrocytes can indeed influence this

Yes, I would say Copaxone is a weakly effective drug (at least as measured in a 2 year trial), but just by adding a small amount of Albuterol results in a relapse rate that is as good or better than the most aggressive immunosuppressive therapy.

This does not guarantee this will halt progression, but from what I've read it has a lot of basis behind it. It would be good to have further studies but for me I'm willing to take a chance.

Again, if you look at the primary endpoint only there was no big difference. If they would have chosen relapse rate as the primary endpoint it would have been considered a breabreakthrough, but the data would be exactly the same. It is only considered as a failure in academic circles and because Albuterol is a Generic drug.

But looking at the history behind this concept, It seems researchers at the University of Chicago investgated the use of beta2-agonists for use in MS a while ago and obtained a patent about their work:

http://www.google.com/patents/US5264459

It's interesting that one of the patentees (Dr. Arnason) was a teacher of Dr. Howard Weiner of Harvard who was an author on the Albuterol trial.

Dr. Arnason (as well as Dr. Weiner) are some of the most respected MS researchers there are, so this does not look like a Zamboni-like discovery:

http://www.nationalmssociety.org/Abo...ch-Goes-To-Pro

I think I am in good hands following their discoveries and reccemdations.

The p value for this data is 0.03. As discussed this is still statistically significant even with the small sample size. But since this is not the pre-defined primary endpoint I guess this can be ignored. But it does not change the fact that it is a real effect.

Good question. I suspect it comes down to a matter of money. Pharma has no interest because Albuterol is a Generic drug and other than them there does not seem to be a viable source of funds for phase 3 trials as you have pointed out.

Maybe the astrocyte as a antigen presenting cell is not involved in the inflammatory cascade. But they seems to think astrocyte dysfunction is involved in progression. This make sense to me because from what I've read the astrocyte provides the majority of the energy to the axons.

yes there are studies for example showing that astrocytes provide lactate to buffer oxidative stress but I think you posed the question originally was "I would also like to hear any disagreements you have with this hypothesis" so you got a few

Yes, I guess the question of whether astrocytes are antigen presenting cells or not is up for debate between Team G and this group. But it looks like other cells in the CNS that are not considered antigen presenting cells can also have this capability, in vivo.

http://www.ncbi.nlm.nih.gov/pubmed/20138112

"Using double immunofluorescence labeling, we show that during acute infection with murinehepatitis virus, MHC class I is expressed in vivo by oligodendrocytes, neurons, microglia, and endothelia,and MHC class II is expressed only by microglia. These data indicate that oligodendrocytes andneurons have the potential to present antigen to Tcells and thus be damaged by direct antigen-specificinteractions with CD8 T lymphocytes."

So it seems their theory is on the right track. I guess time will tell who is right.

It seems the ability of astrocytes to present antigen is indeed controversial but I imagine it is difficult to determine if this is the case in situ during disease.

http://www.sciencedirect.com/science/article/pii/S0925443910001456

"Given the right pro-inflammatory environment with available peptide, astrocytes are capable of priming myelin-specific CD4+ and CD8+ T cells, but whether or not this specific environment occurs during MS or EAE requires more investigation."

in the 1980s, it was shown that virtually every cell type could present antigen especially when treated with gamma interferon and got to a stage when even an interferon-stimulated Wellington Boot can present antigen:-) ,but in vivo this is unlikely not only do cells often not express the MHC antigens but they do not express the necessary co-stimulatory molecules. A lot of effort was spent on astrocyte presentation and a lot of papers wrote about it, but there are plenty of professional APC about

I really welcome this thought process, the idea that a progressive form of the disease there from the start, while there is also an attack based action going on too. In fact - I have something like that happening to me! Tecfidera seems to be holding back the relapses, but something else is marching on. More neurologists need to be open to this type of thinking, no matter if there's a solution right here and now. I had a neurologist that just threw his hands up and said it was all too much for him to work out. My current neurologist is much more involved in the research community and is open to this sort of thought. Even though there's nothing he has to offer me today, I know it makes him open minded enough if something is available tomorrow.

I think it involves autoimmunity at two levels. During RRMS the adaptive immune system predominates, but at the same time the innate immune system is in a state of chronce activation and seems to lead to progression. Over time the nerves become permanently damage and at this point your disability increases.

At the same time, it is not an autoimmune disease because healthy people have autoreactive cells to the same extent as MSers. Because of this many researchers are discovering the nervous system has control over the immune system. The immune system does not function autonomously. Every other system in your body is controlled by the nervous system so why would the immune system be any different.

All immune cells have receptors for chemicals released by the nervous system, so it seems like this is another avenue that immunity/autoimmunity is balanced.

Here is a good review article about this:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396833/

I think many scientist are starting to recognize this as a important component of ms.

Where is the auto-antigen? Kir4.0 was a purported candidate in a NEJM paper but this has been unsubstantiated. Any other candidates? In regards to treating autoimmunity properly, how can this be accomplished? Alemtuzumab depletion followed by autologous stem cell transplant? Are any novel treatment regimens being considered or in trial to stop autoimmunity?

http://www.jci.org/articles/view/80297 Interesting anon 9:01 regarding cross-talk between sympathetic NS and the immune system. It seems cross-talk between nervous system and blood vessels may occur in the retina. Obvious implications for neurodegenerative disease pathology.

Are there any candidates. Things in oligodendrocytes different people will see different things

In regards to treating autoimmunity properly, how can this be accomplished?

In our hands first you have to deplete the T cells and then use your antigen-specifc therapy....don't do this and either it will not work or not work properly. Remember this when we see failures in MS in the future.

Alemtuzmab + stem cells...interesting but i certainly would not use alemtuzumab as it is clearly blocking immune tolerance induction other wise there would not be secondary autoimmunity consequences

Even the microglia which are the cells that seem to be chronically activated in MS have receptors that respond to nervous system input. I think this could be one aspect that is going on in ms. Here is a paper describing this:

http://www.ncbi.nlm.nih.gov/pubmed/17904651

"Microglia are the intrinsic immune cells of the brain and express chemokine and cytokine receptors that interact with the peripheral immune cells. Recent studies have indicated that microglia also respond to the brain's classical signalling substances, the neurotransmitters. Here, we review the evidence for the expression of neurotransmitter receptors on microglia and the consequences of this receptor activation for microglial behaviour. It is evident that neurotransmitters instruct microglia to perform distinct types of responses, such as triggering an inflammatory cascade or acquiring a neuroprotective phenotype. Understanding how microglia respond to different neurotransmitters will thus have important implications for controlling the reactivity of these cells in acute injury, as well as for treating chronic neurodegenerative diseases."

No, your thinking is correct and researchers are comming to the same conclusions:

http://www.ncbi.nlm.nih.gov/pubmed/16214415

"Disease progression in multiple sclerosis (MS)--an inflammatory demyelinating and neurodegenerative disease with a presumed T-cell driven autoimmune origin--has long been hypothesized to be associated with stress. However, this notion has only recently been supported by prospective clinical studies. Several clinical and molecular studies in MS and its animal models have recently shown disruptions in the communication between the immune system and the two major stress response systems, the hypothalamo-pituitary-adrenal (HPA) axis and the autonomic nervous system. Insensitivity to glucocorticoid and beta-adrenergic modulation might be involved in overshooting inflammation in MS, whereas hyperactivity of the HPA axis has been linked to neurodegeneration and increased disability. Here, we integrate findings from molecular, cellular, experimental, clinical and epidemiological research to describe the involvement of stress response systems in MS pathogenesis and progression."

With regard to risk factors previously believed to be involved in MS which will impact cases of MS Children? There PPMS records in children and adolescents? And it would be appropriate to initially treat them with more aggressive therapies, such as alemtuzumab or HTSC?

So there is proof that anxiety and stress worsens and speeds up Ms?Great news for people who get diagnosed with Ms and then get anxious and stressed What's the treatment? Would anti anxiety or anti depressants help?

I think there is strong evidence that stress and the nervous system has an impact on the disease. One hypothesesis is that the there is a problem with the receptors on the immune cells that enable communication with the nervous system.

Keep in mind that stress is not just a state of agitation, but can be other states such as infection that induces biological activity for which the nervous system becomes activated.

For me personally I am following an add on therapy that seems to try to address this issue:

http://activemsers.wssnoc.net/showthread.php?t=1811

Amazingly this therapy has significant reduction in relapse rate in a phase 2 randomized controlled trial, but because relapse rate was not pre-chosen as the primary endpoint this therapy was not considered a success.

Unfortunately, this add on therapy is a generic drug so there is a slim chance it will be investigated further but the data behind it seems to be compelling.

Stress and anxiety can can both trigger relapses and make MS symptoms worsen. Meditation daily, even better twice daily helps reduce stress and anxiety. I would not want to take anti anxiety medication when there is a natural long term option available. Although anti anxiety medication can be useful short term. Yoga also helps reduce stress and I expect pilates does too. Excercise has been shown to reduce stress. It's important that neurologists recognise and acknowledge the connection with stress and MS .

Treatments for anxiety and depression,there are treatments so if you are depressed speak to your health care professionals.Whether agents that affect these co-morbidities help the course of MS I can't say as I don't have the data to hand. MS SMART will examine this through the use of SSRI.

AnonymousSunday, May 10, 2015 1:10:00 p.m. This again a post about beta 2 adrenergic receptors please see elsewhere for comments as it seems unrelated to the post.

Anon 1:16. I am sure neuros recognise problems of stress and MS,the question is what can be done about it.

Treatments for anxiety and depression,there are treatments so if you are depressed speak to your health care professionals.Whether agents that affect these co-morbidities help the course of MS I can't say as I don't have the data to hand. MS SMART will examine this through the use of SSRI.

AnonymousSunday, May 10, 2015 1:10:00 p.m. This again a post about beta 2 adrenergic receptors please see elsewhere for comments as it seems unrelated to the post.

Anon 1:16. I am sure neuros recognise problems of stress and MS,the question is what can be done about it.

Thanks MD. To begin with NICE need to recognise that stress can cause problems in MS. Currently they do not as MS treatment guidelines do not mention about stress. It needs to be added to the treatment guidelines. Experienced neurologists sometimes (but not all) acknowledge stress can cause problems in MS and new trainee neurologists need training in this area.

am I correct in saying testosterone has a positive effect on serotonin levels? Also as does biotin? Ive read a study somewhere to do with tryptophan and biotin, tryptophan having a positive effect on serotonin too?

Am I correct in thinking ssris lower testosterone?With the exception of fluoxetine? If testosterone levels are associated with disability in Ms and people are given ssris surely that could make it worse?

More data neededThere was a very recent EAE( http://www.ncbi.nlm.nih.gov/pubmed/25906771) paper showing it had no real effect on the disease course. There was some data suggesting a symptomatic effect, but it needs repeating.

Prof G mentioned above to treat PPMS early with rituximab and laquinimod. Are these drugs available today to give us ? I also think the McDonald criteria prevents PPMS being diagnosed early enough. I have had suspected PPMS since 2011 when my symptoms and MRI lesion were so mild. I went privately and insisted on MRI as I just knew something was up. There is a lesion but I am still waiting to have enough evidence to get a proper diagnosis!

I don't expect or want a deluge but would this not explain what were referring to? That early treatment with effective anti inflammatory such as the cyclophosphamide and then rituimab would be an option in aggressive early ppms. The aggressive nature would surely suggest an inflammatory stage ?

TGN1412=TAB08. So the answer is clear no it will not be a miracle treatment...the study was a disaster zone and many people lost their fingers and toes because of the disastrous cytokine storm that happened. It is well known that mitogenic CD3 is dangerous and why they would have expected anything different from an agonist anti-CD28 is beyond me...totally predictable.

Mice can tolerate this type of insult as I guess they can tolerate cytokine storms...guinea pigs would be dead in a couple of minutes. They picked the wrong non-human primate to do toxicity tests and the phase I trials was preformed in a non safe manner.

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